This Application is a 371 of PCT/EP00/08876 filed Sep. 8, 2000 which claims foreign priority to Application number 1663/99 filed in Switzerland on Sep. 10, 1999.
The present invention relates to a preparation based on plant extracts which has an antioxidant effect and is particularly useful in the prevention and treatment of circulation and chronic-degenerative problems, and in the prevention and treatment of hypertension.
This object is achieved according to the invention by providing a preparation characterised in that its active ingredients include a combination of Ginkgo biloba biflavones, catechin and/or epicatechin, cumarin and derivatives thereof, and an ingredient chosen from asiaticoside, asiatic acid, madecassic acid and compounds thereof.
This object is achieved according to the invention by providing a preparation characterised in that its active ingredients include a combination of Ginkgo biloba biflavones, catechine and/or epicatechine, cumarine and derivatives thereof, and an ingredient chosen from asiaticoside, asiatic acid, madecassic acid and compounds thereof.
The preparation is obtained by mixing plant extracts which contain the above active principles.
It is known that extracts from the leaves of Ginkgo biloba contain important active principles and in particular flavonol glucosides, lactonic terpenes and dimeric biflavones or flavones. The flavonol glucosides and the lactonic terpenes constitute the active components of standardized Ginkgo biloba extracts currently available on the market and are, respectively, powerful antibxidants and stimulants of nitric oxide and of effective platelet aggregating factor (PAF) antagonists. Thanks to the combined action of the active principles they contain, standard Ginkgo biloba extracts have proved to have a powerful vaso-motor effect, able to improve both central and peripheral blood flow. However, these extracts do not contain the biflavone component which is not extracted during normal processing. The Ginkgo biloba extract used in preparations according to the present invention is highly enriched with the biflavone component and, as a possible option, with extracts containing flavonol glucosides and lactonic terpenes. Five biflavones in particular have been identified in the biflavone component of Ginkgo biloba: these are, in particular, amentoflavone, bilobetine, isoginkgetine, ginkgetine and sciadopisitine; the five said compounds differ only by the presence of methyl compounds in some positions and, like all flavones, are powerful antioxidants. However, from a pharmacological point of view, they are characterised by their anti-phosphodiesterase, anti-inflammatory, vasculokinetic and anti-allergy properties. Phosphodiesterases (PDE) are cell enzymes responsible for interacting with cyclic nucleotides so as to linearize them. Cyclic nucleotides are involved as second messengers in transmitting intercellular signals and are thus responsible for some phenomena which are very important from a biochemical point of view. They assist with the visual process and in the relaxation of smooth muscles, they stimulate lipolysis in adiposity and vasculo-motion in capillary arterioles. More specifically, it is sufficient to report that in inhibiting PDE depending on cyclic AMP, these biflavones demonstrate an IC50 of 1.2 micromoles.
The anti-inflammatory properties of biflavones, and in particular those of amenthoflavone, have been demonstrated both in vitro, by measuring the interaction of these biflavones with cyclo-oxygenase, lipo-oxygenase e phospholipase A2, and in vivo, using various models of inflammation in animals (carragineen oedema, Croton oil inflammation etc). The anti-inflammatory action of biflavones was confirmed both in models using local application and in those in which they were administered intraperitoneally. In these models, the biflavones always demonstrated an anti-inflammatory action equivalent to that of indomethacyn or prednisolone. This effectiveness can be explained by analizing the IC50 of cyclo-oxygenase inhibition, which is 3 micromoles for amentoflavone.
With regard to the microvascularkinetic activity of biflavones, it should be reported that, following acute treatment, these substances improve the size of the arterial sphygma wave and, following chronic treatment they improve capillary density in tissues with trophic-connective problems, such as those affected by panniculopathy and/or various degrees of sclerodermy. Biflavones also have clear anti-allergy properties; they inhibit the release of histamine by mast-cells stimulated by allergens: thereby reducing or countering the formation of oedemas resulting from vasodilation and increases in vascular permeability.
In the context of the invention it is convenient to use an extract of leucocyanidine or leucoanthocyanin derived from Vitis vinifera as the source of catechin or epicatechin. Leucoanthocyanins are procyanidolic oligomers derived from condensing monomeric units of flavan-3-ols and flavan-3,4-diols, these being either free or esterified with gallic acid; leucoanthocyanines are powerful antioxidants. They are able to protect the endothelial wall of vessels and the extra-cellular matrix surrounding capillary wail""s, as well as having anti-atherosclerotic properties owing to their antioxidant action on low-density lipoproteins (LDL) in blood.
The extracts are preferably used in a phytosomal form, in which the active components are complexed with phospholipids.
In the context of the invention, it is convenient to use an extract of leucocyanidine or leucoanthocyanin derived from Vitis vinifera as the source of catechin or epicatechin. Leucoanthocyanins are procyanidolic oligomers derived from condensing monomeric units of flavan-3-ols and flavan-3,4-diols, these being either free or esterified with gallic acid; leucoanthocyanines are powerful antioxidants. They are able to protect the endothelial wall of vessels and the extra-cellular matrix surrounding capillary walls, as well as having anti-atherosclerotic properties owing to their antioxidant action on low-density lipoproteins (LDL) in blood.
These active principles have a good bio-availability even when administered orally and their tropism have been demonstrated for the cardiovascular system and for all tissues, such as artery walls, which are rich in glycoamminoglycene.
Preferably, phytosomal forms of extracts are used, thus further enhancing the bioavailability of the active principles. In this form the procyanidines are complexed with phospholipids, particularly with soya distearoylphosphatidyecholine.
The preferable source of cumarin cumarine is an extract of Meliotus officinea, cumarin and its derivatives being the main active principles thereof; the main active principles of this extract are melilotine (3,4 dihydro-cumarine), melilotic acid (hydroxycumarinic acid), melilotoside (melilotin glucoside) and some flavonoids which act like vitamin P; the active ingredients contained in the extract are particularly effective in increasing capillary strength, in reducing vascular permeability, in stimulating venous circulation and improving lymphatic circulation.
Extract of Melilotus may be replaced or backed up, as a source of cumarine and its derivatives, by an extract of Aesculus hippocastanum (horse chestnut) in the same dosage or up to around twice the dose of Melilotus extract.
The most abundant active ingredient of Aesculus hippocastanum extract, obtained from the bark, the pericarp of the fruit, the leaves or the buds, is cumarine glucoside, esculoside (6-0-glucosil-7-hydroxy-cumarine).
Other cumarins ctziari ies acontained in the extract are fraxine (8-0-glycoside-7-hydroxy-6-mehoxycumarin) and aglicone, esculetine (6,7-dioxy-cumarin) and fraxetine (7,8-dioxy-6-methoxy-cumarin).
The preferred source of asiaticoside, asiatic acid and madecassic acid is an extract containing a triterpene fraction of centella (Centella asiatica) which contains a combination of the above three active principles. The extract should preferably be used in a phytosomal form, obtained by a reaction between the triterpene fraction of the Centella asiatica with a phospholipid. A main action of the triterpene fraction of centella consists in accelerating the uptake and metabolism of lysine and of proline, thus increasing the synthesis and the release of tropocollagen and stimulating the turnover of acid mucopolysaccharides in connective tissue.
The basic composition of the invention can thus be obtained by mixing a Ginkgo biloba biflavone extract (perhaps in combination with a standard Ginkgo biloba extract also containing flavonol glucosides and lactonic terpenes), leucocyanidine extract, Melilotus officinalis extract and Centella extract; these extracts preferably being in a phytosomal form except for the Melilotus officinalis extract.
With reference to the extracts normally available on the market, the basic composition is preferably made up by the following percentages by weight:
2.5-40% Ginkgo biloba biflavone extract;
15-80% of leucocyanidine extract;
2.5-60%, preferably 2.5-30% of Melilotus officinalis and/or Aesculus hippocastanum extract;
2.5-40% of centella extract; possibly in combination with:
2.5-40% of standard Ginkgo biloba extract containing flavonol glucosides and lactonic terpenes. In terms of the content of active principles, the composition of the invention preferably contains the following percentages by weight:
0.2-14%, preferably 0.8-5% of total biflavones, expressed as ginkgetine content,
0.5-16%, preferably 1.5-6% of catechin and/or epicatechin, expressed as catechin content;
0.1-6%, preferably 0.4-2% of cumarin and its derivatives;
0.3-18%, preferably 0.9-6% of asiaticoside;
0.4-26%, preferably 1.4-9 % of asiatic acid and/or madecassic acid;
and possibly one or more of the following substances:
0.2-10%, preferably 0.6-4%, of flavonol glucosides and
up to 1.3-2%, preferably up to 0.5%, of ginkgolide lactonic terpenes (bilobalide).
The composition can also contain active ingredients chosen from gamma-linolenic acid, eicosapentaenoic acid (EPA), docohexaenoic acid (DHA), ruscogenin and/or neoruscogenin, flavinoids such as vitexine, hyoside, proanthocyanidine, epicatechin and crategolic acid and mixtures thereof.
Gamma-linolenic acid is preferably introduced into the preparation in borage oil, added in quantities of 50 to 180% by weight with reference to 100 parts of basic mixture.
The preferred source of eicosapentaenoic acid (EPA) and of docohexaenoic acid (DHA) is fish oil which, with reference to 100 parts of the basic composition, may be added in quantities of 25 to 120% by weight.
The preferred source of ruscogenin and/or neoruscogenin is an extract of Ruscus aculeatus (Butcher""s broom), this extract is preferably added in quantities of 5 to 50% by weight, with reference to 100 parts of the basic mixture.
The preferred source of flavonoids is an oily maceration of hawthorn Crataegus oxyacantha which, with reference to 100 parts of the basic mixture, can be added in quantities from 25 to 100% by weight.